Progress in Microbes and Molecular Biology 1 Review Article The Bioprospecting of Anti-Vibrio Streptomyces species: Prevalence and Applications Loh Teng-Hern Tan1,2, Learn-Han Lee1,4*, Bey-Hing Goh3,4* 1Novel Bacteria and Drug Discovery (NBDD) Research Group, Microbiome and Bioresource Research Strength Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. 2Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, PR China. 3Biofunctional Molecule Exploratory (BMEX) Research Group, School of Pharmacy, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. 4Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Bandar Sunway 47500, Selangor, Malaysia Abstract: Vibrio sp. has been a major pathogen that resulted in difficult to treat infections, and greatly impacting the aqua- culture industry. Thus, more effective approaches are needed to overcome this problem. Bacteria of the genus Streptomyces is a group of prolific producers for various bioactive compounds. Streptomyces species with antibacterial activity against Vibrio sp. have been reported from numerous studies, indicating that Streptomyces could be a good candidate for treatment of Vibrio infections. This review aims to provide an overview on the distribution of the Streptomyces with anti-Vibrio activity from diverse geographical locations. Furthermore, this review also highlighted that Streptomyces sp. can be a great source for anti-Vibrio agents to control vibriosis, such as in the aquaculture settings. Keywords: Streptomyces, Vibrio sp., secondary metabolites, antibacterial, biocontrol agent Received: 18th May 2019 Accepted: 15th June 2019 Publish Online: 05th July 2019 * Correspondence: Bey-Hing Goh, goh.bey.hing@ monash.edu. School of Pharmacy; Learn-Han Lee, lee. learn.han@monash.edu, leelearnhan@yahoo.com. Je- ffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia. Citation: Tan LTH, Lee LH, Goh BH, The bioprospecting of anti-Vibrio Streptomyces species: prevalence and applications. Prog Microbes Mol Biol 2019; 2(1): a0000034 INTRODUCTION Seafood is rich in nutritional values, serving as a healthy food choice for major protein source in human diet. For the past decades, the accelerated growth in commercial aquaculture for total seafood supply is growing in folds in order to satisfy the increased demand for seafood globally [1]. However, seafood is prone to various contaminants, such as pathogenic microorganisms which include bacte- ria, viruses, fungi and parasites [2-7]. These pathogens are posing high risk for seafood and water borne illnesses in consumers [8-11]. This is because seafood can be a vehicle for pathogens. Vibrio sp., which is one of the genera from Bacteria kingdom [12], has been associated with gastro- enteritis and wound infections in human [13], such as V. vulnificus [14], V. parahaemolyticus [15] and V. cholerae [16]. Foodborne Diseases Active Surveillance Network (Food- Net) reported that in the year 2018, Vibrio sp. have inflict- ed 537 cases of infections with 1.1 incidence per 100,000 population in United States. FoodNet also indicated that the number of Vibrio infection cases have increased sig- nificantly by 109% in 2018 when compared with previ- ous reported cases within the year 2015 to 2017 [17]. Furthermore, Vibrio sp. have also inflicted several major outbreaks worldwide [18-20]. For instance, the biggest out- break of cholera was reported in Haiti on October 2010 with more than seven thousand deaths recorded for the first time in more than a century [21]. Besides causing infections in human, Vibrio species is also a great threat towards aquaculture by causing vibriosis that hampers the fishery industry growth and causes serious economic losses globally. The etiological agents of vibriosis include V. harveyi, V. alginolyticus, V. anguillarum, V. salmonicida, V. mimicus and V. para- haemolyticus [22]. These pathogens have been reported to cause mortalities up to 100% in aquaculture. For example, the V. harveyi has caused mass mortality of black tiger shrimp Penaeus monodon by causing lumi- nous vibriosis [23-25]. Another species V. mimicus is also responsible for epidemic in catfishes in China with high mortality rate between 80 to 100% [26]. Consequently, Copyright 2019 by Tan LTH et al. and HH Publisher. This work under licensed under the Creative Commons Attribution-NonCommer- cial 4.0 International Lisence (CC-BY-NC 4.0) 2 antibiotics are used as prophylactic measures or to treat the established infections in the culture systems due to the immense impact of vibriosis in aquaculture. How- ever, antibiotic resistant strain of pathogens are emerging due to the routine and uncontrolled usage of antibiotics and leading to therapeutic failure of existing antibiotic [27]. Therefore, it necessitates the search for more effec- tive alternatives to overcome this problem. In this re- gards, recent efforts have been evidenced in bioprospect- ing for natural products derived from plant [28-32], animal [33] or microbial origins [34] with promising antimicrobial effects to facilitate future development of new strategies against the antibiotic resistant strains of Vibrio. The interest on the discovery of bioactive compounds from microbial origin is increasingly attractive towards the researchers, especially from the extreme environ- ments. This is because that the sea and soil microbiota are frequently exposed to the complex, fluctuating and competitive environments which is believed to be the driving forces for metabolic pathway adaptation and lead to production of valuable metabolites [35-39]. The extremely diverse and unsurpassed richness of the sec- ondary metabolism exhibited by Streptomyces has made these filamentous bacteria to serve as a rich bioresource for valuable bioactive compounds [35, 40-43]. Ever since the discovery of streptomycin as the first therapeutically ben- eficial antibiotic in 1944 [44], Streptomyces species have been known to synthesize enormous amount of bioactive secondary metabolites, including antibiotics, antitumor agents, antiparasitic, immunosuppressive agents and in- dustrially important enzymes [34, 45, 46]. The genus Strepto- myces is ubiquitously found in soil. In fact, they are also found to inhabit in wide range of niches such as in the aquatic environments, marine dwelling animals [47] and as symbionts of plants [48] and insects [49]. Therefore, we attempted to evaluate the potential of Streptomyces as a source of antibiotics against the antibiotic-resistant strains of Vibrio. This review discusses the current knowledge on the Streptomyces as a promising biocontrol agent of Vibrio and assesses their distribution, isolation, secondary metabolites production. Figure 1 depicts the potential of Streptomyces bacteria as a source for anti-Vibrio metabo- lites and their application in aquaculture. The Bioprospecting of Anti-Vibrio... Figure 1. The summary of the potential of Streptomyces bacteria as a source for anti-vibrio biocontrol agent and its application as probiotic in aquaculture. 1. Streptomyces sp. has been isolated from different ecosystems, including both terrestrial and aquatic environments. The percentage on the pie chart illustrates the proportion of Streptomyces strain with anti-Vibrio activity from respective ecosystem. (Percentage of isolation from specific sources from both ecosystems are provided in the text) 2. The anti-Vibrio active metabolites produced not only exhibits direct killing or growth inhibitory effect against Vibrio pathogens, specific mechanisms are also demonstrated such as anti-virulence, anti-biofilm and anti-quorum sensing activity against Vibrio pathogens. 3. Streptomyces also exhibits the potential to be used as biocontrol agent in aquaculture for prevention of vibriosis. VIBRIO sp. AND VIRULENCE FACTORS Being one of the six genera for the family Vibrionace- ae, the genus Vibrio are Gram-negative, halophilic and curved-rod in shape [50]. They are ubiquitous inhabitants of the warm coastal and estuarine waters as well as in the gut of filter-feeding shellfish. There are at least 12 species of Vibrio have been known to be pathogenic and cause foodborne diseases in human [51]. Besides capable to cause massive pandemics resulting in many cases of infections and deaths worldwide, some of the Vibrios are known to be pathogenic to aquatic organisms, such as finfish, shellfish and corals [52]. Virulence factors are the unique molecular features pos- sessed by pathogen for colonisation, nutrient acquisi- tion, infection and damage to a host [53]. Studies have identified numerous virulence factors from the genus Vib- rio, including pathogenic V. cholerae, V. parahaemolyticus and V. vulnificus. For example, the cholera toxin (CTX), a well-known virulence factor or enterotoxin produced by V. cholerae [54], the thermostable direct hemolysin (tdh) and the tdh-related hemolysin (trh) in V. parahaemolyticus [15] and capsule polysaccharide (CPS) in V. vulnificus [55]. All these virulence factors are attached on the surface of the cells or are secreted into the extracellular environment. To transport these virulence factors, specific secretion system is essential to facilitate the delivery of the effector virulence factors into host cells from the bacterial cells. For instance, the type III secretion systems (T3SS1 and T3SS2) are the well characterized systems play significant roles in the pathogenicity of Vibrio pathogens. Studies demonstrated that regulation of virulence gene expression could be the 3 critical aspect for pathogenicity. To illustrate, a higher ex- pression of those virulence genes could render a bacterial strain to be virulent, but this may not often be the case. As pathogenicity of bacteria is not always dependent on the presence of virulence genes [58]. Quorum sensing (QS) is a machinery adapted by bacteria to coordinate the expression of certain genes, including those encoding virulent pheno- types, through the mediation of small signalling molecules [56]. For examples, the N-acylhomoserine lactone and the multi-channel QS systems are the two common QS sys- tems acquired by the Vibrio bacteria [57, 58]. There are many strategies used to control Vibrio infections, including the antibiotics, water disinfectants, vaccines, im- munostimulants, bacteriophages and probiotics in aquacul- ture [59-61]. Despite that, new antibiotics or chemotherapeu- tic approaches are needed to cope with the ever-increasing evidences of antibiotic resistance among the Vibrio sp. Be- sides that, inhibition of the virulence factors of the patho- gens is an alternative to kill the Vibrio pathogens such as the disruption of bacterial cell-to-cell signalling or quorum sensing and the development of antagonistic compounds (antivirulence therapy) that specific targeting the virulence machinery of Vibrio pathogens. Hence, it is important to fully understand the virulence regulation mechanism (de- scribed earlier) in order to identify better therapeutic tar- gets for prevention of outbreaks caused by Vibrio patho- gens. In this review, Streptomyces bacteria is suggested as the promising candidate for the management of Vibrio pathogens based on the potential of Streptomyces bacteria in the production of anti-Vibrio compounds and its applica- tion in aquaculture. EMERGENCE OF ANTIBIOTIC RESISTANT VIBRIO sp. Given the excessive use of antibiotics for the past few de- cades, the emergence and the ever-increasing prevalence of antimicrobial resistant pathogens is of a great concern in global health [27, 62-64]. Today, many of antibiotics have been totally restricted in agriculture and aquaculture of de- veloped countries due to the enormous detrimental impacts on the environment [65, 66]. Despite that, the unrestricted use of antibiotics remains in countries with growing scale of agriculture and aquaculture industries such as China, Chile and Thailand. The antibiotics were used prophylactically by most of the farmers from aquaculture and agriculture settings to prevent or treat disease outbreaks, particularly infections caused by Vibrio bacteria. For instance, exces- sive and frequent use of antibiotics as preventive manage- ment was observed from shrimp farming in Thailand [62]. A total of 86% of the shrimp farmers from Thailand were reported highly dependent on antibiotic use as a preventive measure, 14% of the farms even used antibiotics in a daily basis. Norfloxacin, oxytetracycline, enrofloxacin and sul- phonamides were the commonly used antibiotics in shrimp farms [62]. Frequent use of antibiotic is also widely evident in other regions, including Mexico [67], Italy [27], Philippines [68] and China [69]. Undoubtedly, the enormous misuse of antibiotics has re- sulted the ever-increasing reports of multi-drug resistant Vibrio species in aquaculture settings and marine environ- ments [70]. For instance, a recent study showed the presence of Vibrio sp. resistant to β-lactam and tetracycline in the hemolymph of Litopenaeus vannamei shrimp [71]. Fur- thermore, a plasmid mediated tetracycline resistant V. parahaemolyticus was isolated from shrimps infected with acute hepatopancreatic necrosis disease (AHPND), indicating the presence of antibiotic resistance that can potentially be transferred through transposition, con- jugation and plasmid uptake to other bacterial species in the same environment [72]. The disease AHPND, also known as early mortality syndrome, is one of the major threats to shrimp farming. The disease has caused se- vere mortality up to 100% in aquaculture of P. vannamei and P. monodon [73, 74]. Recently, Castillo et al. (2015) [75] reported a draft genome sequence of V. parahaemo- lyticus strain VH3 isolated from farmed amberjack in Greece. The strain VH3 was found to possess multidrug resistance efflux pumps and antibiotic resistant genes for fluoroquinolones and tetracycline [75]. Moreover, V. parahaemolyticus has also been reported to be resistant to numerous classes of antibiotics such as penicillins (ampicillin), aminoglycosides (amikacin, kanamycin, streptomycin), cephalosporins (cefotaxime, ceftazi- dime, cefazolin) [76, 77], quinolones (ciprofloxacin, nali- dixic acid), macrolides (azithromycin, erythromycin) and chloramphenicol [78, 79]. Besides the antibiotic resistance incidences occur in aquaculture, there are enormous number of literatures focus on the antibiotic resistance of V. cholerae [80, 81], the causative agent of cholera which is an infectious di- arrheal disease associated with hypovolemic shock and rice watery stools. This bacterium appears to be a re- emerging problem to human worldwide, causing many disease outbreaks in which constant monitoring for their ever-changing antibiotic resistance profile is required. Over the years, multidrug resistant V. cholerae has been reported from many regions of the world especially the under-developed and developing countries, including Bangladesh [82], India [83], Africa [84], Haiti [85] and Viet- nam [86]. Reports have shown that clinical isolates of V. cholerae have become resistant to numerous antibiotics including tetracycline [87], ampicillin [88], nalidixic acid [89], streptomycin, sulphonamides, trimethoprim, gen- tamicin [90] and ciprofloxacin [89]. V. cholerae is a natu- rally competent bacterium containing a highly diverse genome (genomic plasticity), readily taking up external DNA and possibly recombine into their genome [91]. The antibiotic resistance in V. cholerae was attributed to target modification or acquisition of resistance gene cassettes from mobile genetic elements (MGE). Both integrative conjugative elements (ICE) and superinte- gron are known to be the major source of conferring an- tibiotic resistance in V. cholerae. For instance, the SXT element, an ICE responsible for gene translocation, is found in V. cholerae encoding various antibiotic resis- tance genes such as chloramphenicol, sulphamethoxa- zole, trimethoprim and streptomycin [92]. In fact, these SXT and closely-related elements are present in almost all V. cholerae clinical isolates and some environmental isolates from Asia and Africa [93]. A group of researcher has confirmed that the SXT elements were the vectors of genes conferring multidrug resistance in Chinese epi- demic O1 V. cholerae to tetracycline and trimethoprim- sulfamethoxazole [94]. Taken together, the resistance development limits the useful lifespan of antibiotic and Tan LTH et al. 4 results in the requirement for a constant introduction of new antibacterial compounds [95, 96]. STREPTOMYCES sp. AS POTENTIAL SOURCE FOR ANTI-VIBRIO AGENT The genus Streptomyces (phylum: Actinobacteria) are soil- dwelling Gram-positive bacteria with high G+C (70%) genomic content. They have characterized filamentous growth involving tip extension and filamentous branching which eventually form network of filaments named as sub- strate mycelium [97, 98]. Interestingly, Streptomyces possess a remarkably complex developmental cycle [99]. Under en- vironmental stress and solid cultivation condition, they are capable to switch from vegetative phase (substrate myce- lium) into a reproductive sporulation phase (aerial hyphae mycelium) [100]. The secondary metabolites are produced at the end of the active vegetative growth and during the dormant or reproduction stage [101]. More than 70 years ago, streptomycin was discovered as the first therapeuti- cally beneficial antibiotic produced by S. griseus [44]. To- day, Streptomyces bacteria remain to be prolific sources of novel secondary metabolites with diverse range of bio- logical activities such as antibacterial, antitumor, antivi- ral, antifungal, immunosuppressive activity, antifeedant, insecticidal and neuroprotective activity [45, 102]. Numerous studies have also described the production of valuable en- zymes and compounds by Streptomyces with industrially and clinically importance [45, 103, 104]. The enormous biosynthetic capabilities of Streptomyces have made them an irreplaceable resource for microbial natural products in microbial world [105]. The Streptomy- ces derived secondary metabolites are structurally diverse and based on different backbone structures, including polyketides, β-lactams, peptides and pyrroles [42, 101]. For example, the bioactive compounds include glycopeptides (vancomycin, teicoplanin, telavancin) [106], angucycline (tetrangomycin, landomycin, urdamycin) [107], tetracycline (chlortetracycline, oxytetracylcine, demeclocycline) [108], phenazine (saphenamycin, endophenazine, phenazinomy- cin) [109], macrolide (erythromycin, spiramycin, oleando- mycin) [110], aminoglycoside (streptomycin, kanamycin, tobramycin) [111], benzoxazolophenanthridine (jadomycin) [112] and oligosaccharides (flambamycin, avilamycin, cura- mycin) [113]. Majority of the Streptomyces derived secondary metabo- lites are known to be antibiotics, given that they are needed for inhibiting the growth of other competing microorgan- isms present in the same environment [114]. The production of secondary metabolites also involves in the symbiotic in- teractions between the Streptomyces and the plants. There are strains of saprophytic Streptomyces colonize the plant roots and even in the plant tissues. The antibiotics pro- duced by Streptomyces protect the host plant from potential pathogens while the symbionts provide nutrients for Strep- tomyces development [48]. Terrestrial soils are the classical habitats of Streptomyces sp. but current evidences indicate that Streptomyces can be isolated from marine soils as well [42, 115]. These soils are known to be complex environments with many stressors such as diverse and variable nutrient availability, huge fluctuation in temperature, pH and salin- ity [116]. As a group of non-motile microorganism, Strepto- myces species requires to evolve and adapt for the sur- vival in the diverse environmental challenges. Bentley et al. (2002)[117] explained the large genome (>8Mbp) of Streptomyces sp. that encoding regulators, transport proteins and enzymes render them to be resistant to those environmental stressors. In 2001, Streptomyces coelicolor A3(2) was reported to possess a more than 8 Mega base pairs linear chromosome as the first and largest ever sequenced microbial genome [117]. A large proportion of the genome was shown to contain regula- tory genes which are likely to be involved in detection of, and response to extracellular stimuli and stresses [117]. Furthermore, approximate 23 cluster of the genes consisted of 4.5% of the total genome were found to be encoded for the biosynthetic enzymes that produce wide range of secondary metabolites. Ikeda et al. (2003)[118] further revealed a larger secondary metabolic gene clus- ter covering approximately 6% of the genome found in S. avermitilis ATCC31267. The genome of Streptomyces is significantly larger as compared to the recent reported 5.1 Mega base pairs chromosome from the genus Bacil- lus. Also as one of the best characterized bacterial gen- era, the genus Bacillus has been extensively exploited for biotechnological use in the food and pharmaceutical production [119]. In the light of the expanding knowledge of microbial genetics and genomics, genome mining has revealed the potential of Streptomyces sp. in synthesiz- ing a large diversity of compounds that have yet to be identified via the detection of numerous cryptic novel secondary metabolite biosynthetic gene clusters [120, 121]. Overall, these interesting features of Streptomyces have demonstrated that this genus is a very good candidate for bioprospection of bioactive compounds with anti- bacterial properties [122], especially in anti-Vibrio activity as the main focus of this review. STUDIES OF STREPTOMYCES WITH ANTI- VIBRIO ACTIVITY Up to the year 2015, based on the data reported from 64 studies (Table 1), there are around 128 strains of Strep- tomyces exhibited antibacterial activity toward Vibrio sp. Two and 3 strains of Streptomyces were shown to exhibit antivirulence and antibiofilm activity against Vibrio sp., respectively. Table 1 tabulates the number of Streptomyces strains with anti-Vibrio activity with different stages of work performed ranging from the preliminary screening stage to an in-depth characteriza- tion of a Streptomyces strain exhibiting anti-Vibrio ac- tivity. Based on these studies, Streptomyces strains with anti-Vibrio activities have been isolated from diverse ecosystems ranging from terrestrial to marine environ- ments, and from marine organisms to aquatic plants. As depicted in Table 1, 80% of the studies revealed Strep- tomyces strains with anti-Vibrio activities were isolated from aquatic environments while the remaining 20% of the studies showed Streptomyces with anti-Vibrio activi- ties were derived from terrestrial origin. Majority of the studies (48.3%) isolated Streptomyces with anti-Vibrio activity from marine and mangrove sediment, followed by marine organisms such as sponges, coral and fishes (21.7%), terrestrial soils (18.3%), aquatic plants (6.7%), water (3.3%) and terrestrial plants (1.7%). Among the 128 strains of Streptomyces with antibacterial activity The Bioprospecting of Anti-Vibrio... 5 against Vibrio sp., 116 strains (90%) were isolated from aquatic environment. This data suggests that marine eco- system could be more preferable source for isolation of Streptomyces with anti-Vibrio activity as compared to the samples collected from terrestrial regions. Despite that, it cannot be disregarded that terrestrial soil could be a po- tential source for Streptomyces strains with anti-Vibrio activity. In fact, some interesting Streptomyces strains with anti-Vibrio activity were reported from terrestrial soils [123, 124]. Table 1. Different isolation sources of Streptomyces with anti-Vibrio activity. Source of isolation Country Locations Number of Streptomyces with anti-Vibrio activity isolated The identified Streptomyces sp. with anti-Vibrio activity References Marine sediment India Andaman Island 6 Streptomyces sp. MKS-09 (S. xantholiticus) Streptomyces sp. MKS-13 (S. aureofascicus) Streptomyces sp. MKS-17 (S. galtieri) Streptomyces sp. MKS-24 (S. vastus) Streptomyces sp. MKS-35 (S. galbus) Streptomyces sp. MKS-39 (S. rimosus) [125] Sediment from coastal area of Thondi, Palk Bay (Lat. 9o45’N, Long. 79 o3’E) 1 Streptomyces sp. S8-08 (S. albus DQ333301.1 99%) [126] Chennai coast area, Tamilnadu 1 Streptomyces ECR3 [127] Vellar Estuary, Tamilnadu 3 Streptomyces sp. F1 Streptomyces sp. F2 Streptomyces sp. F3 [128] ns 1 Streptomyces sp. isolate 6 [129] Royapuram, Muttukadu, Mahabalipuram seashores, Adyar estuary 2 Streptomyces sp. C11 Streptomyces sp. C12 [130] Near-sea shore sediment from Palk bay, (Lat. 9 o44’10”N, Long. 79 o10’45”E) Southeast coast of Thondi, Tamilnadu 1 Streptomyces sp. (99% S. fradiae BDMS1) [131] Visakhapatnam, India 1 Streptomyces sp. KS1908 [132] Andaman and Nicobar Islands (11o38’42.8”, 92o42’30.7”) 5 Streptomyces sp. NIOT-VKKMA02 (100% S. griseus) Streptomyces sp. NIOT-VKKMA26 (100% S. venezuelae) [133] Bay of Bengal 1 Streptomyces sp. LCJ94 [134] Bay of Bengal (Lat. 11o42’23.15”N, Long. 79o46’57.97”E) 1 Streptomyces sp. SS7 [135] Saltpan soil sample from Parangipettai Potnovo (Lat. 11o30’N, Long. 79o46’E) Cuddalore district, Tamilnadu 1 Streptomyces sp. DPTD215 (98% S. noursei AY999827) [136] Versova coast, Mumbai (Lat. 19 o28’26.32”N, Long. 72o48’07.21”E) 1 Streptomyces sp. MVCS6 (KC292198) [137] Versova coast, Mumbai (Lat. 19o08’26.12”N, Long. 72o48’07.41”E) 1 Streptomyces sp. MVSC13 (KC292199) [138] China Submarine sediment from Sanya Bay (109o32’E, 18o11’N), northern South China sea 1 Streptomyces sp. SCSIO 01689 (98.3% S. sanyensis) [139] Sediment from shrimp farms Hainan Island, China Marine 7 Streptomyces sp. A03, A05 (S. cinerogriseus - majority antagonistic to Vibrio sp.) Streptomyces sp. A26, A42 (S. griseorubroviolaceus) Streptomyces sp. A41 (S. lavendulae) Streptomyces sp. A45 (S. roseosporus) Streptomyces sp. B15 (S. griseofuscus) [140] Viet- nam Sediment from shrimp culture pond in Thua Thien Hue 1 Streptomyces sp. A1 HM854225 [141, 142] Korea Seaweed rhizosphere and sediment (10m depth) from coast of Korea 1 Streptomyces sp. PK288-21 (99% S. atrovirens DQ026672.1) [143] Egypt Coastal lagoon sediment from Sinai Peninsula 1 S. ruber ERKH2 [144] Cuba Near-shore sediment from Matanzas, Villa Clara, Cienfuegos and Ciego de Avila, Central provinces of Cuba. 3 [145] Tan LTH et al. 6 Austra- lia Queensland, (Lat. 21o43’09”S, Long. 149o25’54”E) 3 Streptomyces sp. CLS-28 Streptomyces sp. CLS-39 Streptomyces sp. CLS-45 [146] Man- grove sediment/ rhizo- phere soil/es- tuarines India Mangalavana, Narakkal, Puthuvyppu, (9o55’10o10’N and 76o10-76o20’E ns ns [147] Sundarbans, India and Bangladesh ns ns [148] Velar estury, Tamilnadu, India (lat. 11.4900oN Long.79.7600oE) 1 Streptomyces sp. MA7 [149] East coast region, Pichavaram mangrove forest (Lat. 11.43oN, Long. 79.77oE) Tam- ilnadu, India 2 Streptomyces sp. ECR64 Streptomyces sp. ECR77 (accession number KF158225) (S. labe- dae) [150-152] Bonnie camp & Kalash, (Lat. 21o51’05.823” N, Long. 88o38’27.021” E) & (Lat. 22o00’25.599” N, Long. 88o42’13.948” E), Sundarbans, India 3 Streptomyces sp. SMS_7 (closely related to S. tendae ATCC19812T) Streptomyces sp. SMS_SU13 (96.59% similarity to S. labelae NBRC 15864T, S. variabilis NBRC 12825T, S. erythrogriseus LMG 19406T) Streptomyces sp. SMS_SU21 (99.75% similarity to S. griseorubens NBRC 12780T) [153] Water sample India Aquaculture water from Vellore, Tamilnadu 4 ns [154] Seawater from Visakhapatnam 1 S. rochei MTCC 10109 [155] Marine sponges India marine sponges (Callyspongia diffusa, My- cale mytilorum, Tedania anhelans, Dysidea fragilis) from Vizhinjam port, (Lat. 8o22’30”N, Long. 76o59’,16”E) south west coast India. 10 Streptomyces sp. AQBCD03 Streptomyces sp. AQBCD11 Streptomyces sp. AQBCD24 Streptomyces sp. AQBMM35 Streptomyces sp. AQBMM49 Streptomyces sp. AQBTA66 Streptomyces sp. AQBDF81 [156-158] Kovalam coast, West coast of Kerala (8o23’N, 76o57’E). ns ns [47] China Mycale sp. from sea area of Gulei Port, Fujian, China (Lat. 23.74, Long. 117.59) 3 HNS054 (99% S. labedae) HNS049 (S. microflavus) HNS056 (S. flaveus) [159] Egypt Red Sea 1 Streptomyces sp. HC9 (accession number JQ929061) 97% Strepto- myces rochei SBPL-21 [160] Marine corals India Mucus of coral, A. digitifera from Hare Island (9o12’N,79o5’E), Gulf of Mannar, Tamilnadu 6 Streptomyces sp. CA3 (99.8% S. akiyoshiensis FJ486367.1) Streptomyces sp. CA4 (96.7% Streptomyces sp. EU523135.1) Streptomyces sp. CA5 Streptomyces sp. CA9 Streptomyces sp. CA15 Streptomyces sp. CA18 (96.7% Streptomyces sp. EU523135.1) [161] China Gorgonian coral (E. aurantiaca, M. squa- mata, M. flexuosa, S. suberosa, V. umbracu- lum) from Sanya coral reef conservation (18o11’N, 109 o25’E), South China sea 3 Streptomyces sp. ZXY018 Streptomyces sp. ZXY077 Streptomyces sp. ZXY090 [162] Lu Hui Tou fringing reef 3 SCSIO 11527 (S. fimicarius ISP5322 100%) SCSIO 11469 (S. rutgersensis NBRC 12819 100%) SCSIO 11531 (S. variabilis NBRC 12825 99.859%) SCSIO 11717 (S. viridodiastaticus NBRC 13106 100%) [163] Fishes India Ornamental fish, Chaetodon callare (red tail butterfly), Archamia fucata (orange-lined cardinal) from Vizhinkam port, India Vizhinjam port, (8o22’30”N, 76 o59’16”E) southwest coast of India 7 AQBCC06 AQBCC 20 AQBCC 24 AQBCC 40 AQBCC 51 AQBCC 54 AQBCC 75 [164] Marine - Epinephelus diacanthus (grouper), estuarine - Oreochromis mossambicus (tilapia), fresh-water - Cyprinus carpio (common carp) from Vizhinjam, Veli, Centre for Aquatic and Research Extension ns Streptomyces sp. [165] Red snapper from Tamilnadu ns ns [166] The Bioprospecting of Anti-Vibrio... 7 Sea plants and animals in the intertidal zones China Shark (Mustelus manazo) local market, marine plant animal - sea hare (Aplysia dactylomela), sea anemone (Actiniaria) and sea plant (Ulva lactuca, Enteromorpha, Gracilaria verrucosa) from Xiamen Island 5 Streptomyces sp. A4 Streptomyces sp. A9 Streptomyces sp. A16 Streptomyces sp. A18 Streptomyces sp. A29 [167] Marine algae/see- weeds India Intertidal rocky surfaces of Muttom coast, south west coast of india (Lat. 8o7’15”N, Long. 77o1’E) 25 AQB.SKKU 8 (S. coelicolor) AQB.SKKU 10 (S. autotrophicus) AQB.SKKU 18 (S. pedanensis) AQB.SKKU 20 (S. deccanensis) AQB.SKKU 25 (S. vinaceus) AQB.SKKU 37 (Streptomyces nov. sp.) [168-170] Terres- trial soil sediment Iran Grassland, orchards, vegetable fields from Kerman, Hormozgan, Sistan and Balooches- tan, south and south east provinces of Iran 1 Streptomyces sp. 419 [171] India Rhizosphere soil from Shikaripura, Kar- nataka 3 SRDP-S-03 SRCP-S-05 SRDP-2-30 [172] Rhizosphere soil from Thirthahalli, Shiva- mogga, Karnataka, India 1 SRDP-07 [173] Similipal Biosphere Reserve (21o28’ to 22o08’ N, 86o04’ to 86o37’ E) 1 Streptomyces sp. SS2 [174] Forest soils from Western Ghats region, Kanyakumari District (Lat. 8o03’ to 8o35’N, Long. 77o15’ to 77o36’ E) 3 Streptomyces sp. ERI-1 Streptomyces sp. ERI-3 Streptomyces sp. ERI-26 [124, 175] Thai- land Agricultural soil from Sakonnakhon Province 1 Streptomyces sp. No.87 [176] Chile Desert soil (Salt falt, zero vegetation cover, hyper-arid) from Atacama desert (Salar de Atacama, Laguna de Chaxa) (23o17’S, 68o10’W) 1 Streptomyces leeuwenhoekii sp. nov. C34T DSM42122 [123] Chili field soil from Chittagong, Bangladesh 1 Streptomyces sp. MU9 [177] Terrestri- al plant Austra- lia Snakevine plant (Kennedia nigriscans) from Aboriginal community of Manyallaluk, SE of Katherine, Nothern Territory (14o16’352” S, 132o49’750”E) 1 Streptomyces sp. NRRL30562 [178] *ns – not specified Tan LTH et al. There were significant lower number of studies reported Streptomyces with anti-Vibrio activity from the terrestrial environments as compared to the much higher number of studies on the marine Streptomyces. The higher isola- tion rate of Streptomyces strains from marine environment could be due to the recent interest of researchers toward the marine natural products discovery as many novel bacteria genus and species with production of novel compounds have been identified from the marine environment [179-181]. In another context, these phenomena seem to imply that the resources which can be accessed easily had been exhausted as extensive studies on the terrestrial soil derived microor- ganisms were observed over the years. The recurrent iso- lation and screening of the predominant species from the environments have resulted in rediscovery of known com- pounds which is a major problem faced in drug discovery. As reported, similar well-known and structurally-related antibacterial compounds were discovered from the Strepto- myces isolated from different terrestrial environments [182]. To support the hypothesis that marine Streptomyces is a better source for anti-Vibrio activity, comparison be- tween the efficacy of the metabolites produced by the anti-Vibrio Streptomyces isolated from respective envi- ronments were performed. To render easier inter-study comparison, the anti-Vibrio activity of the Streptomy- ces from each study was represented by the highest in- hibition zone reported. The efficacy of the anti-Vibrio metabolites produced by Streptomyces isolated from respective source was obtained based on the median in- hibition zone of respective site of isolation. These anti- Vibrio Streptomyces strains were then categorized into four different groups based on their source of isolations. According to Table 2, it shows that the strength of anti- Vibrio activity displayed by each group and the ranking is as follow, mangrove sediment (21.0 mm) > marine organisms (plants and animals) (18.0 mm), terrestrial soil (18.0 mm) > marine sediment (15.01 mm). The anti- Vibrio Streptomyces isolated from the respective isola- tion source with differential strength against Vibrio sp. were discussed as follow. 8 Table 2. Comparing the anti-Vibrio efficacy of Streptomyces from different envi- ronment sources. Source of isolation Median of inhibition zone (mm) Terrestrial soil 18.00 (n = 7) Marine sediment and water 15.01 (n = 10) Mangrove soil 21.00 (n = 3) Marine organisms 18.00 (n = 8) Terrestrial environments The number of undiscovered antimicrobials from Strep- tomyces and the estimated number of antibiotics still be discovered from Actinobacteria could be well above 105 as predicted with the use of mathematical models [183]. Fur- thermore, new species of Streptomyces are being identified every day, indicating that our knowledge on this genus is still far from exhaustive. Hence, continuous effort has to be put into the exploitation of Streptomyces from terrestrial regions by taking advantage of underexplored ecological niches as demonstrated by several groups of researchers that discovered Streptomyces with anti-Vibrio activity. This study identified a total of 11 strains of Streptomyces with anti-Vibrio activity were found from different types of ter- restrial soils and an endophytic Streptomyces isolated from a terrestrial plant [178]. The Streptomyces with anti-Vibrio activity were isolated from a wide variety of the terrestrial soils ranging from the commonly accessible agriculture soils [176], forest soils [124], grassland and orchard soils [171, 177] to the more extreme environments such as the hyper arid desert soil [123] and arctic sediments [184]. The detailed locations for the sources of isolation of the Streptomyces with anti-Vibrio activity were described in Table 1. Rateb et al. (2011)[123] reported a desert soil de- rived Streptomyces strain C34 produced rare 22-mem- bered macrolactone polyketides, known as chaxalactins A-C (1-3) with anti-Vibrio activity. A recent report de- termined that this Streptomyces strain C34 represents a new species and named as Streptomyces leeuwenhoekii sp. nov., a strain showing high potential for drug discov- ery with total genome size of around 7.86Mb [185]. The site of isolation of this novel species of Streptomyces is from the hyper-arid and high-attitude Atacama Desert located in Chile (23o17’S, 68o10’W). The three macro- lactone polyketides including the chaxalactins A (1), B (2) and C (3) displayed a minimum inhibitory concen- tration of 12.5, 20 and 12.5μg/mL against the pathogen V. parahaemolyticus NCTC10441 [123] which was iso- lated from the feces sample of a patient with gastroen- teritis. The molecular structures of the chaxalactins were depicted in Figure 2. Meanwhile, an endophytic Strepto- myces NRRL30562 isolated from snakevine plant (Ken- nedia nigriscans) was found to produce newly described antibiotics, named as munumbicin B (4), C and D [struc- tures of munumbicin C and D have not been elucidated]; that displayed antibacterial activity against V. fischeri PIC345 with inhibition zones measured at 16mm, 9mm and 12mm respectively at 10μg concentration [178]. The Bioprospecting of Anti-Vibrio... Figure 2. Chemical structures of bioactive compounds with anti-Vibrio activities. 9 Besides the direct antagonism of Streptomyces against Vib- rio sp. by direct killing of the microorganism or imped- ing microbial growth, the bioactive products derived from Streptomyces sp. also exhibited activity that interferes with the expression of pathogenic traits of Vibrio pathogens [186, 187]. Augustine et al. (2012)[184] reported the 20% culture su- pernatant of strains Streptomyces A733 and A745 isolated from arctic sediment (Ny-Alesund, an island in Svalbard Archipelago (79o55’N, 11o56’E) reduced the biofilm for- mation of V. cholerae O1 MCV09 by 88% and 80% respec- tively. Furthermore, an antivirulence compound, known as guadinomine B (5) was produced by a strain Streptomyces sp. K01-0509 isolated from soil sample collected from the Amami Oshima, Kagoshima, Japan [186]. The guadinomine B (5) was reported to be potent in inhibiting the type III se- cretion system (TTSS) of gram-negative bacteria, including most of the pathogenic Vibrio sp. that utilize this appara- tus for protein secretion and translocation as their primary virulence mechanism with IC50 at 14nM [188]. Another study showed that the soil-derived S. mobaraensis DSM40847T from Mobara city, Japan, produced endoprotease inhibi- tors that against cysteine protease papain which is known to be virulence factors involved in bacterial pathogenicity [187]. The endoprotease inhibitor was known as Streptomy- ces papain inhibitor (SPI) which exhibits inhibitory effect on the growth of wide range of Gram-positive and Gram- negative bacterial pathogens. The addition of 10µM of SPI was shown to be bactericidal toward V. cholerea serotype O1 (ATCC 14035). This study suggested that SPI could be a potential novel broad-spectrum antimicrobial agent for clinically relevant infectious diseases [187]. Aquatic environments Marine environments are the largest source of microbes and new secondary microbial metabolites. The marine sources ranging from the seashore soil sediments to the depths of 10,000 metres [189] are rich sources of microbes. Furthermore, marine environment contains wide range of distinct microorganisms that are not present in terrestrial environment [45, 190, 191]. This may be attributed to the ex- tremely different physical and chemical conditions as com- pared to the terrestrial conditions. It has been suggested that marine Actinobacteria exhibit distinct characteristics from those terrestrial counterparts and therefore produce more potentially novel bioactive compounds [190, 192]. Thus, marine environment is a potential source for isolation of novel Actinobacteria in which increasing evidences on the discovery of novel antibiotic and industrially important en- zyme from marine Actinobacteria [193-196]. Likewise, 80% of the reviewed studies demonstrated the isolation of Strepto- myces with anti-Vibrio activity from aquatic environments such as marine sediments, marine invertebrates and man- grove ecosystems. Marine sediments Based on the literatures collected, a total of 38 strains of Streptomyces with anti-Vibrio activity were isolated from marine sediments of diverse geographical locations. These diverse geographical locations include coastal lagoon sedi- ment [144], near-shore sediment [131], shrimp culture pond [146] and submarine sediment (45m underwater) [139]. Strep- tomyces species found in virgin soil is expected to pro- duce broad-spectrum antimicrobial compounds, hence rendering them to be successful in outcompeting others and effectively colonize the newly formed soil. Mitra et al. (2011)[197] suggested that the specific area favorable for obtaining maximum number of isolates with broad- spectrum activity in an estuarine setting is limited to the narrow band between the mean high and low tide marks. In brief, the samples collected from sites influenced by tides were suggested to exhibit a high antagonistic po- tential [198]. Mitra et al. (2008)[198] believed that antibacte- rial compound is required to aid in colonizing a newly formed top soil during the transition periods between high and low tides, thereby the periodic oscillations of dry and wet conditions trigger more antagonistic activ- ity of Actinobacteria. In agreement with observations of Mitra et al. (2011)[197], several marine sediment derived Streptomyces strains exhibiting broad antibacterial spec- trum and surfactants producing ability were isolated from area constantly affected by tidal gradient in Minnie Bay, A & N islands, India [199]. Furthermore, the high nutrient availability and osmotic flux in the sampling site could be another reason for the broad-spectrum activities exhibited by these strains. For example, the ethyl acetate extract of the Streptomyces sp. NIOT-VKKMA02 displayed the maximum inhibitory activity against a classical O1, hy- pertoxigenic strain V. cholerae 569B (MTCC3904) with 20 mm inhibition zone measured at concentration of 50 μg [199]. Furthermore, studies demonstrated the purified DOPA melanin produced by Streptomyces sp. MVSC13 and MVCS6 isolated from the marine sediment of Ver- sova coast, Mumbai, India (Lat. 19o28’26.32”N, Long. 72o48’07.21”E) exhibiting strong antibacterial activity against several fish and human Vibrio pathogens [137, 138]. Specialized media (Tyrosine asparagine medium) was employed to cultivate Streptomyces sp. MVSC13 and MVSC6 for the production of DOPA melanin which dis- played good activity against Vibrio sp. FPO5 (from in- fected region of Carassius auratus, 16S rRNA 98% V. parahaemolyticus) (15±0.01mm), V. fluvialis RMMH10 (12±0.02mm), V. splendidus RMMH11 (9±0.02mm), V. parahaemolyticus RMMH12 (15±0.03) [137, 138]. Moreover, a new pyranosesquiterpene compound (6) was discovered from a strain Streptomyces sp. SCSIO 01689 isolated from submarine sediment, located 45m underwater of northern South China Sea (18o11’N, 109o32’E). The iso- lation of Streptomyces sp. SCSIO 01689 and the prepara- tion method for its production of cyclic peptide type com- pounds were patented [139]. The patent disclosed the cyclic peptide type compounds, pyranosesquiterpene compound (6), Cyclo(D)-Pro-(D)-Ile (7), Cyclo(D)-Pro-(D)-Leu (8) and Cyclo(D)-trans-4-OH-Pro-(D)-Phe (9) exhibited potent anti-Vibrio activity, specifically against V. anguil- larum with MIC measured at >100, 0.05, 0.04 and 0.07 μg/mL. Besides that, You et al. (2007)[200] indicated the metabolite of Streptomyces sp. A66 isolated from marine sediment was found to be effective in reducing the devel- opment of antibiofilm in Vibrio sp. The strain attenuated the biofilm formation of V. harveyi with 99.3% of inhibi- tion rate and 74.6% of degradation rate at concentration of 2.5% (v/v) [140]. Another study also indicated that the antibiofilm activity of Streptomyces sp. A66 involved in the inhibition of the quorum sensing system of Vibrio sp. by reducing the N-acylated homoserine lactones activity Tan LTH et al. 10 [200]. The N-acylated homoserine lactones are responsible for the coordination of virulence expression in response to density of surrounding bacterial population [200]. Mangrove environment Mangroves are located along the intertidal zones of estu- aries, backwaters, deltas, marshes and mudflats along the tropical and subtropical regions. Mangrove ecosystem is a unique ecological niche which contains highly produc- tive and diverse microbial community [201-204]. Similarly, the mangrove environment has been known to be potent res- ervoir for isolation of antibiotic-producing Actinobacteria [205]. Eccleston et al. (2008)[206] revealed that the ecology has great impact on the diversity of Actinobacteria. Higher population of Actinobacteria was isolated from mangrove mud sediments than the benthic communities associated with littoral sand sediments, freshwater creek and lake habitats. Eccleston et al. (2008)[206] suggested the low num- bers of Actinobacteria from freshwater habitats and littoral sand sediments could be attributed to the low organic nu- trient levels as compared to high nutrient habitats such as mangrove mud [206]. Accordingly, Hong et al. (2009)[35] also demonstrated the abundance of bioactive strains is corre- lated with ecological influences. A low number of bioactive strains was recorded from soil containing more sand and less organic matter while rhizosphere soil was rich source of bioactive strains [35]. By comparing the different isolation sources, the data showed that the Streptomyces strains derived from man- grove soil displayed the strongest antibacterial activity against Vibrio sp. with the highest median inhibition zone (21.0 mm), followed by marine sediment (15.0 mm), ma- rine organisms (18.0 mm) and terrestrial soil (18.0 mm). This observation suggests that mangrove environments provides a better site for isolation of Streptomyces strains with 39.9% higher anti-Vibrio activity than those from ma- rine sediment and water. Mohana and Radhakrishnan (2014)[149] reported an anti- Vibrio Streptomyces sp. strain MA7 from mangrove rhi- zosphere sediment collected from Vellar estuary region at Parangipettai, Tamilnadu, India (11.4900oN; 79.7600oE). Strain MA7 displayed antibacterial activity towards sev- eral Vibrio sp. pathogens including V. mimicus, V. cholerae O1, V. cholerae O139 and V. parahaemolyticus. The metha- nol extract of strain Streptomyces sp. MA7 exhibited strong antibacterial activity against V. parahaemolyticus with 21 mm inhibition zone measured at concentration of 250 μg [149]. Furthermore, an aliphatic compound named as N-iso- pentyltridecanamide was identified from the ethyl acetate extract of strain Streptomyces ECR77 (16S rRNA 99% S. labedae) isolated from the mangrove sediment of East coast region, Pichavaram mangrove forest (Lat. 11.43oN, Long. 79.77oE). The ethyl acetate extract of Streptomyces ECR77 showed the maximum inhibitory activity against V. chol- erae, V. parahaemolyticus and V. alginolyticus with inhibi- tion zones 13.66±0.47mm, 9.66±0.94 and 16.33±0.47mm measured at 25 μL concentration [152]. Similarly, Sengupta et al. (2015)[153] isolated three mangrove derived anti-Vibrio Streptomyces in Sundarbans, they displayed high antibac- terial activity against V. cholerae (MCTC 3906) with the inhibition zone measured more than 25 mm and minimum inhibitory concentration at 50 μg/mL. Marine animals and plants Streptomyces species is also found to form symbioses with other organisms, most notably plants and invertebrates. In many cases, Streptomyces species showed protective mutu- alistic symbioses with the host in which the host provides nutrients and protections for the bacteria while the bacte- ria produce antibiotics to protect host from pathogens [49, 207]. Researches have indicated marine invertebrates which are sessile, such as sponges and corals are great sources of marine bioactive metabolites. These bioactive metabolites in these marine organisms were produced by the marine bioactive metabolite producing microorganisms as symbi- otic relationships. For instance, theopaulauamide, an anti- fungal bicyclic glycopeptide isolated from Palauan sponge, Theonella swinhoei has been confirmed to be originated from a novel delta-proteobacterium known as Candidatus Entotheonella palauensis, served as one of the first experi- mental evidences for microbial derived compounds from sponge [208]. There has been an increasing evidence of sponges and cor- als as the potential sources for isolation of Streptomyces with anti-Vibrio activity. The comparison made earlier re- vealed that the Streptomyces isolated from marine organ- isms, such as sponges and corals, represent alternative sources for anti-Vibrio Streptomyces. These Streptomy- ces were isolated from marine sponges such as the Cal- lyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis collected from Vizhinjam port (Lat. 8o22’30”, Long. 76o59’16”E) located at Southwest coast of India [157]. The ethyl acetate extracts of these Streptomyces strains exhibited diverse strength of antibacterial activity toward both human and fish Vibrio pathogens such as the V. harveyi, V. parahaemolyticus and V. alginolyticus with maximum inhibition zone measured up to 30 mm at 50 μg concentration [156]. Su et al. (2014)[159] reported the isolation of Streptomyces sp. HNS054 (16S rRNA 99% similarity to S. labedae) from marine sponges, Mycale sp. collected from Gulei Port, Fujian, China (Lat. 23.74, Long. 117.59) exhibiting antibacterial activity against both V. parahaemo- lyticus and V. diabolicus, with 10-15 mm inhibition zone observed against V. parahaemolyticus. The study sug- gested that Streptomyces sp. strain HNS054 may play an important in conferring a chemical defensive mechanism to protect the sponges from pathogenic Vibrio sp. which are associated with mortality of marine animals [159]. The detection of these Streptomyces strains with secondary me- tabolite production further support the facts that sponges or marine invertebrates are important source of biologically active compounds [209, 210]. Coral is also a potential source to isolate Streptomyces sp. with genetic capacity to produce diverse potentially bio- active molecules which may contribute to the chemical defense of coral holobionts [162, 163]. There were 4 studies (6%) reported the isolation of Streptomyces with anti-Vib- rio activity from different species of corals, including the Acropora digitifera [211], Melitodes squamata [212], Porites lutea, Galaxea fascicularis [213], Sarcophyton glaucum [160]. Li et al. (2014)[213] reported a total of four different spe- cies of Streptomyces with anti-Vibrio activity in the coral The Bioprospecting of Anti-Vibrio... 11 samples collected from Lu Hui Tou fringing reef (18o13’N, 109o28’E). The ethyl acetate extracts of these Streptomy- ces showed different degree of anti-Vibrio activity against both pathogenic V. coralliilyticus ATCC BAA-450 isolated from diseased coral Pocillopora damicornis and V. algi- nolyticus serotype XII ATCC 17749 isolated from spoiled horse mackerel which caused food poisoning. The high- est anti-Vibrio activity was displayed by Streptomyces sp. SCSIO11717 (16S rRNA 100% S. viridodiastatitus NBRC13106) with zone of inhibition of 12.3±2.5mm mea- sured at 20 mg/mL as compared to the standard drug, cipro- floxacin (20 mg/mL) with 15±1mm against the pathogenic V. alginolyticus [213]. Furthermore, Streptomyces sp. SCSIO 11527 (16S rRNA 100% S. fimicarius) with anti-Vibrio ac- tivity isolated from coral Galaxea fascicularis was positive for PKS-II gene with 90% similarity to ketoacyl synthase from S. argillaceus, suggesting its potential in producing anthracycline-related compounds [163]. This finding was supported with one of the previous study demonstrated the production of nanaomycins A (10) and D (11) by Strep- tomyces rosa var. notoensis OS-3966 isolated from a soil sample collected at Nanao-shi in Noto Peninsula, Japan [214]. The study showed that both nanaomycins A (10) and D (11), anthracycline/anthraquinone antibiotics exhibited strong inhibitory activity against both marine pathogens, V. alginolyticus 138-2 and V. parahaemolyticus K-1 [214]. Besides marine sponges and corals, seaweed is also an- other source for anti-Vibrio Streptomyces. There were 3 studies reported the presence of Streptomyces with anti- Vibrio activity from seaweeds collected from intertidal rocky surfaces at Muttom coast, Southwest coast of India (8o7’15”N, 77o1’E) [170]. According to Hollants et al. (2013) [215], the macroalgal-bacterial interactions are not unusual. In fact, it has been evidenced that the production of anti- microbial compounds by the microorganism is to protect the algae surface from pathogens, herbivores and fouling organisms. Interestingly, a strain Streptomyces sp. strain AQB.SKKU20 derived from seaweed was expressing an- tagonistic activity towards Vibrio sp. after the exposure to ethidium bromide, suggested that the mutations induced by ethidium bromide stimulates antibiotic production [168]. Furthermore, study also indicated that Streptomyces with anti-Vibrio activity isolated from seaweeds could be used as probiotics and biocontrol agents against vibriosis in aquaculture [169]. This study demonstrated that the incor- poration of the anti-Vibrio strains of Streptomyces in the probiotic feed resulted in higher percentage of survival rate of Macrobrachium rosenbergii prawn juveniles with no external disease manifestations after challenged with pathogenic V. vulnificus at 105 CFU/mL which caused up to 79.2% mortality in control group with no Streptomyces as probiotic [169]. APPLICATION OF ANTI-VIBRIO COM- POUNDS PRODUCING STREPTOMYCES sp. IN AQUACULTURE Streptomyces sp. constitute a group of industrially and clin- ically important microorganisms [40, 42, 115, 216] that produce valuable compounds including antibiotics [41], antitumor agents, antiparasitic, immunosuppressive agents and en- zymes [45]. Being the fact having an immense potential for bioactive secondary metabolites production, Streptomyces has the advantage of producing potential antagonistic and antimicrobial compounds can be valuable as biocontrol agent against Vibrio pathogens in aquaculture [217]. The production of antagonistic compounds renders Strepto- myces sp. capable to compete for nutrients and attach- ment sites in the host. For example, Streptomyces sp. was reported to produce siderophores which could influence the growth of pathogenic Vibrio sp. [140]. Siderophores are ferric ion-specific chelating agents which aiding the Streptomyces sp. to compete for iron in the aquatic envi- ronment [218]. Studies have indicated that the intracellular iron concentration is essential for biofilm formation and development in bacteria and also the Vibrio sp. [219-221]. Mey et al. (2005)[221] revealed the wild-type V. cholerae suffered poor biofilm formation in iron-deficient medium and also elucidated the role rhyB gene in iron homeostasis to biofilm formation as the rhyB mutant V. cholerae was unable to form wild-type biofilm in low-iron medium. Biofilm formation plays many imperative roles in Vibrio sp. for their survival, virulence and environmental stress- ors resistance [53]. Biofilms serve to render Vibrio sp. more protected and less susceptible to antimicrobial agents and hence difficult to control. The discovery of Streptomyces strains with ability to produce siderophores is providing a new approach in controlling Vibrio sp. in aquaculture settings as biofilms are considered a reservoir for some pathogenic Vibrio sp. that can cause detrimental effects on the cultured livestock in aquaculture. Moreover, studies also revealed the production inhibitory compounds with anti-quorum sensing [200] and anti-virulence activities [186] targeting Vibrio sp. by Streptomyces sp. These promising anti-Vibrio activities also further strengthen the view of the applicability of Streptomyces in aquaculture as an al- ternative biocontrol agent against Vibrio sp. [217]. CONCLUSION There is an urgent need to search for new therapeutic drugs, especially antibiotics due to the rapid increase of resistance in Vibrio sp. pathogens to the major front- line antibiotics. Thus, extensive effort is required by the researchers focusing on the screening and isolation of promising strains of Streptomyces with antimicrobial properties. The information and knowledge obtained in this review could help in selecting the potential sources of isolation and as a guide for future bioprospectors in find- ing antibiotic-producing Streptomyces, especially against Vibrio spp. Based on the findings of this review, man- grove sediment could be a better source for Streptomyces with anti-Vibrio activity. Nevertheless, there is still lim- ited studies on the investigation of the exact antibacterial mechanisms of these Streptomyces derived bioactive me- tabolites against the Vibrio pathogens. Therefore, future studies on the elucidating the antibacterial mechanisms of these Streptomyces are warranted. As a whole, these anti-Vibrio Streptomyces represent a valuable source for future development of clinically important drugs to treat infections caused by V. cholerae, V. parahaemolyticus and V. vulnificus in clinical settings as well as to be applied as probiotics to control vibriosis in aquaculture. Tan LTH et al. 12 Author Contributions The literature review and manuscript writing were per- formed by LT-HT, L-HL and B-HG. L-HL and B-HG founded the research project. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments This work was supported by the Monash University Malay- sia ECR Grant (5140077-000-00), MOSTI eScience Fund (02-02-10-SF0215 and 06-02-10-SF0300). Reference 1. Hixson SM, Fish nutrition and current issues in aquaculture: the balance in providing safe and nutritious seafood, in an environmentally sustain- able manner. J Aquac Res Dev 2014; 5(234): 2. 2. Law JW-F, Ab Mutalib N-S, Chan K-G, et al., Rapid methods for the detection of foodborne bacterial pathogens: principles, applications, ad- vantages and limitations. Front Microbiol 2015; 5: 770. 3. 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